Glutamine synthetase, cumulative inhibition

Cumulative Feedback Inhibition In cumulative feedback inhibition, the end products can inhibit the reaction of the target enzyme separately. Many textbooks erroneously indicate that the cumulative feedback inhibition of E. coli glutamine synthetase involves separate regulatory sites for each feedback inhibitor. See Cumulative Feedback Inhibition... 

The activity of glutamine synthetase is also controlled by reversible covalent modification —the attachment of an AMP unit by a phosphodiester bond to the hydroxyl group of a specific tyrosine residue in each subunit (Figure 24.26). This adenylylated enzyme is less active and more susceptible to cumulative feedback inhibition than is the deadenylylated form. The covalently attached AMP unit is removed from the adenylylated enzyme by phosphorolysis. The attachment of an AMP unit is the final step in an enzymatic cascade that is initiated several steps back by reactants and immediate products in glutamine synthesis. 

Most of the pathways of amino acid biosynthesis are regulated by feedback inhibition, in which the committed step is allosterically inhibited by the final product. Branched pathways require extensive interaction among the branches that includes both negative and positive regulation. The regulation of glutamine synthetase from if. coli is a striking demonstration of cumulative feedback inhibition and of control by a cascade of reversible covalent modifications. 

Woolfolk, C. A. Stadtman, E. R. (1967). Regulation of glutamine synthetase III. Cumulative feedback inhibition of glutamine synthetase from Escherichia coli. Arch. Biochem. Biophys. 118,736-755. 

Cumulative Feedback Regulation. In this case, each end product causes a partial inhibition or repression when present in excess alone but all end products must be present to effect complete blockage. The most well known example is the inhibition of glutamine synthetase in E. coli by eight end products (Stadtman, 1966). 

Cumulative The first common step enzyme is inhibited indepently (residual activity, Ai) by each of the end products at saturation cone. The simultaneous presence of the saturation cone, of two or more end products results in the ultimate inhibition such that the total residual activity, A, = HAi. Glutamine synthetase is subject to cumulative feedback inhibition by the end products, carbamyl phosphate, Trp, AMP and CTP. 

---